Project Summary: My goal is to become an independent physician-scientist engaged in basic research with clinical relevance. My training thus far in medical oncology and cancer research has laid a strong foundation for an academic career. This grant proposal will enable me to make the transition to independence through an integrated program focused on lab research and supplemented by seminars and scientific discussion forums. All activities will be conducted under the mentorship of my sponsor, Elizabeth Blackburn, and with the guidance of an Advisory Committee of senior faculty experts in my field. My research interests are in the field of telomerase and cancer. Telomerase enzyme lengthens and protects the telomeres at the ends of chromosomes through the combined action of its catalytic subunit (hTERT) and its RNA subunit (hTer). Telomerase is an attractive therapeutic target because, relative to normal cells, telomerase is highly activated in cancer cells and critical to cancer cell proliferation. Our lab has developed a novel telomerase-targeting gene construct that inhibits cancer cell proliferation specifically and effectively. The construct takes a two-pronged approach: It employs siRNA to knock down endogenous hTer, and it encodes a mutated telomerase RNA subunit (MT-hTer) in its place. When expressed in cancer cell lines, MT-hTer integrates with hTERT and forms an aberrant telomerase enzyme that induces rapid DMAdamage, apoptosis, and cell cycle arrest. In this proposal, we hypothesize that the rapid and robust apoptotic response elicited by MT-hTer can effectively inhibit tumor growth. This hypothesis will be tested using mechanistic and translational studies. Specifically we will: 1. Identify the protein components of the MT-hTer-induced apoptotic cascade;2. Use tumor- derived primary cell culture models to assess the pro-apoptotic effects of MT-hTer alone and in combination with established therapies;and 3. Use mouse models to test for tumor-inhibition by MT- hTer delivered systemically with cancer-targeting immunoliposomes. Relevance: The proposed project will characterize a novel telomerase-targeting agent capable of killing a variety of cancer cell types. Its mechanism of action will be explored, and its ability to inhibit metastatic cancers in mice will be tested, thus developing a promising new treatment strategy.